During the last decade, significant attention has been directed towards identification of small non-coding RNAs (sncRNAs) and their biological functions (for review, see Esteller, (2011) Nat Rev Genet 12:861-874), references cited herein are detailed at the end of the Examples]. sncRNAs are 16-35 nucleotides (nts) long and of several classes including microRNA (miRNA), small interfering RNA (siRNA), piwi-interacting RNA (piRNA), etc. Among them, miRNA and siRNA are the most extensively studied, and both suppress gene expression by complementary binding to target mRNAs. The role of sncRNAs in regulating antiviral innate immune responses has just emerged and is largely unexplored (Skalsky et al., (2010) Annu Rev Microbiol 64:123-141).
Discovery of new types of sncRNAs has been greatly facilitated by the development of ultra-throughput sequencing (also called next generation sequencing or deep sequencing) technologies. Numerous sncRNAs have been captured and mapped to various origins, such as mRNA (messenger), rRNA (ribosomal), tRNA (transfer), and sncRNA (small nucleolar RNA), indicating that they are derived from these long RNAs. However, their biological significance remains largely unknown. Although a substantial fraction of sncRNAs might be simply degradation intermediates or by-products during RNA turnover, recent studies have demonstrated that some sncRNAs are actually functional molecules with specific biogenesis (reviewed in Tuck et al., (2011) Trends Genet 27:422-432).
sncRNAs derived from tRNAs, also called tRNA-derived RNA Fragments (tRFs), have been recently identified by several research groups (reviewed in Sobala et al., (2011) Wiley, Interdiscip Rev RNA 2:853-862). There is increasing evidence that they are not by-products from random degradation, but functional molecules. First, tRFs are produced through specific cleavage of tRNA by endonucleases such as angiogenin (ANG), Dicer, and ELAC2 (Emara et al., (2010) J Biol Chem 285:10959-10968, Yamasaki et al., (2009) J Cell Biol 185:35-42, Cole et al., (2009) RNA 15:2147-2160, Lee et al., (2009) Genes Dev 23:2639-2649). Second, tRF expression is regulated either by cellular stresses (Emara et al., (2010) J Biol Chem 285:10959-10968, Yamasaki et al., (2009) J Cell Biol 185:35-42) or cell proliferation (Lee et al., (2009) Genes Dev 23:2639-2649). Third, some tRFs are functional, having trans-silencing activity or being necessary for cell proliferation (Lee et al., (2009) Genes Dev 23:2639-2649, Haussecker et al., (2010) RNA 16:673-695).
Respiratory tract infections (RTIs) are the second leading cause of death worldwide in children less than 5 years old. The majority of RTIs are caused by viruses, among which a paramyxovirus called respiratory syncytial virus (RSV) figures prominently (reviewed in Hermos et al., (2010) Clin Lab Med 30:131-148, Papenburg et al., (2010) Rev Med Virol 20:245-260). Nearly all children have had RSV infection by 2-3 years of age (Glezen et al., (1986) Am J Dis Child 140:543-546). RSV infection also increases the morbidity and mortality rate in immunocompromised patients and the elderly, resulting in a substantial health burden (Falsey et al., (2005) N Eng J Med 352:1749-1759). There is currently no specific treatment or vaccine for RSV infection. Although a prevention strategy has been developed using a humanized monoclonal antibody directed to an epitope of the F protein of RSV, less than 3% of the at-risk infant population has access to this kind of prevention (Martin et al., (2007) Natl Vital Stat Rep 56:1-103).
The role of sncRNAs, especially miRNAs, in host-virus interaction has been documented (Liu et al., (2010) Virology 398:57-67, Hess et al., (2011) BMC Microbiol 11:45). Upon viral infection, host cells alter their sncRNA expression profile as a defense mechanism. On the other hand, viruses can circumvent host defense and promote their propagation by altering cellular sncRNA expression or by expressing their own sncRNAs (Boss et al., (2010) Curr Opin Microbiol 13:540-545, Dolken et al., (2009) Virus Genes 38:355-364, Pfeffer et al., (2004) Science 304:734-736, Reese et al., (2010) J Virol 84:10344-10353). Nonetheless, most of these studies have focused on the role of miRNAs in viral infection, while other types of sncRNAs remain largely unexplored.